This project is designed to establish novel treatments to decrease the risk of PTOA, and to investigate new diagnostic tools to identify patients at high risk of PTOA. The goal is to provide effective immediate preclinical information to support clinical application of these treatments and diagnostic tools. The treatments of interest are: 1) cytoprotective treatment that prevents immediate necrotic and acute apoptotic chondrocyte death at/near a site of acute cartilage injury, and 2) chondrocyte metabolic enhancement treatment developed to improve chondrocyte energy production, to restore anabolic function, and to suppress catabolic activities, by modulating the injury-related acute inflammatory response. These treatments will be piloted using a survival rabbit model. In this model, after controlled surgical insults that replicate major factors contributing to pathogenesis of human PTOA following joint injuries (i.e., acute joint injury and excessive cumulative mechanical stress to the injured cartilage), progressive cartilage loss predictably develops in the experimental joints (knees) in a relatively short period (8 weeks). Using this animal model of rapid-progression PTOA, work is proposed to test if the above treatments are capable of mitigating the early biologically mediated disease process of PTOA in vivo, and whether the treatments effectively decrease subsequent cartilage loss. The diagnostic tools of interest are: 1) MR imaging that visualizes/measures inflammatory anatomical changes and early intra-cartilage degenerative changes prior to cartilage loss, and 2) molecular biomarker analysis that measures whole-joint inflammation and whole-joint cartilage metabolic activity. The diagnostic power of these clinically applicable non- or minimally-invasive tools will be tested in a goat survival model of acute cartilage injury (created by means of precisely controlled blunt impaction insult). Work is proposed to test if these tools are capable of characterizing the severity of acute joint injury in vivo (particularly focusing on cartilage damage), and to test if subsequent progression of cartilage loss in these joints is reliably predictable using the early (< 1 month) information provided by these diagnostic tools.